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Journal of Lipid Research, Vol. 48, 2020-2027, September 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes

Jin-ichi Ito^*, Yuko Nagayasu^*, Kuniko Okumura-Noji^*, Rui Lu^*, Tomo Nishida^*, Yutaka Miura, Kiyofumi Asai, Alireza Kheirollah^*,, Seiichi Nakaya^* and Shinji Yokoyama^1,*

^* Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Bioregulation and Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
Department of Biochemistry, Medical School, Ahvaz Jondishapour University of Medical Sciences, Ahvaz 45-61355, Iran

Published, JLR Papers in Press, June 4, 2007.

¹ To whom correspondence should be addressed. e-mail: syokoyam{at}med.nagoya-cul.ac.jp

Fibroblast growth factor-1 (FGF-1) is secreted by astrocytes and stimulates apolipoprotein E (apoE)-HDL biogenesis by an autocrine mechanism to help in recovery from brain injury. In apoE-deficient mouse astrocytes, FGF-1 stimulated cholesterol biosynthesis without enhancing its release, indicating a signaling pathway independent of apoE biosynthesis upregulation. SU5402, an inhibitor of FGF receptor, inhibited FGF-1-induced phosphorylation of MEK, ERK, and Akt, as well as all the apoE-HDL biogenesis-related events in rat astrocytes. LY294002, an inhibitor of phosphatidylinositide 3-OH kinase (PI3K) and of Akt phosphorylation, inhibited apoE-HDL secretion but not cholesterol biosynthesis, whereas U0126, an inhibitor of MEK and of ERK phosphorylation, inhibited cholesterol biosynthesis but not apoE-HDL secretion. Increase of apoE-mRNA by FGF-1 was not influenced by either inhibitor. When rat apoE/pcDNA3.his was transfected to transformed rat astrocyte GA-1 cells that otherwise do not synthesize apoE (GA-1/25), FGF-1 did not influence apoE-mRNA, but did increase the apoE secretion and Akt phosphorylation that were suppressed by LY294002. Lipid biosynthesis was increased by FGF-1 in GA-1/25 cells and suppressed by U0126. FGF-1 upregulates apoE-HDL biogenesis by three independent signaling pathways. The PI3K/Akt pathway upregulates secretion of apoE/apoE-HDL, the MEK/ERK pathway stimulates cholesterol biosynthesis, and an unknown pathway enhances apoE transcription.

Supplementary key words astrocytes • apolipoprotein E-high density lipoprotein • PI3K • Akt • MEK • ERK

Abbreviations: apoE, apolipoprotein E; CNS, central nervous system; DPBS, Dulbecco's phosphate-buffered saline; ERK, extracellular signal-regulated kinase; FCS, fetal calf serum; FGF-1, fibroblast growth factor-1; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; PI3K, phosphatidylinositide 3-OH kinase; PKB, protein kinase-B

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				Y. Nagayasu, J.-i. Ito, T. Nishida, and S. Yokoyama Reactivity of Astrocytes to Fibroblast Growth Factor-1 for Biogenesis of Apolipoprotein E-High Density Lipoprotein is Down-regulated by Long-time Secondary Culture J. Biochem., May 1, 2008; 143(5): 611 - 616. [Abstract] [Full Text] [PDF]